New application of HUWE1 inhibitor BI8622

An inhibitor, a technology for inhibiting inflammation, applied in the field of medicine, can solve problems such as no research reports, and achieve the effect of inhibiting activation and reducing cell death events

Active Publication Date: 2020-07-03
KUNMING INST OF ZOOLOGY CHINESE ACAD OF SCI
View PDF1 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] BI8622 was screened by Stefanie Peter et al. It can specifically inhibit the ubiquitin ligase HUWE1 through the ubiquitination modification function, and found that it has a certain inhibitory effect on tumorigenesis and development (Peter S, Bultinck J, MyantK, Jaenicke LA, Walz S, Müller J, et al.Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1ubiquitin ligase.EMBOMol Med.2014; 6:1525–1541.), but there is no research report that HUWE1 inhibitor BI8622 can be used to inhibit Inflammasome activation

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • New application of HUWE1 inhibitor BI8622
  • New application of HUWE1 inhibitor BI8622
  • New application of HUWE1 inhibitor BI8622

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The effect of BI8622 on three activated inflammasomes and cell death of NLRP3, AIM2, and NLRC4 in primary mouse BMDM cells.

[0040] Materials and Methods:

[0041] Preparation of primary mouse BMDM cells: euthanize C57 / BL mice of appropriate age (such as 4-6 weeks), separate the femur and tibia under sterile conditions and place them in PBS buffer, scrape off the bone with a scalpel For the muscle, cartilage and epiphysis on the surface, cut both ends of the bone to expose the bone marrow cavity, use a 1mL syringe to absorb DMEM-F12 medium to wash the bone marrow cavity, collect cells, and after the cells are blown evenly, count and adjust the cell density to 1-2Million / mL, add 20ng / mL of M-CSF growth factor in DMEM-F12 complete medium, seed the cells in the cell culture plate, in 5% CO 2 , CO at 37°C 2 Cultivate in an incubator, and collect adherent cells after static culture for 5 days for corresponding experiments.

[0042] The test compound BI8622 was formulate...

Embodiment 2

[0049] The effect of BI8622 on the activated NLRP3, AIM2 and NLRC4 inflammasomes and cell death in human THP1 cells.

[0050] THP1 cells are human mononuclear macrophages, the culture condition is 1640 medium plus 10% FBS, and the specific culture method can be according to the conventional method. The test compound BI8622 was formulated with dimethyl sulfoxide (DMSO) as a storage solution with a concentration of 10 mM, and was diluted to a working concentration of 10 uM with 1640 complete medium before treating the cells. The control group was treated with 0.1% DMSO, and the experimental group BI8622 and the control group The treatment time of both groups was 3 hours, and then the subsequent stimulation and detection experiments of inflammasome stimulators were carried out.

[0051] The inflammasome stimulators were: 1) lipopolysaccharide (LPS) + adenosine triphosphate (ATP) to activate the NLRP3 inflammasome; 2) double-stranded DNA (dsDNA) to activate the AIM2 inflammasome; ...

Embodiment 3

[0057] The effect of BI8622 on activated NLRP3, AIM2, NLRC4 inflammasomes and cell death in primary human PBMC cells.

[0058] Peripheral blood mononuclear cells (PBMC) were separated by density gradient centrifugation to obtain peripheral blood mononuclear cells (PBMC) [approved by the Life Science Ethics Committee of Kunming Institute of Zoology, Chinese Academy of Sciences, number: SMKX-20191201-01]. The isolated PBMC cells are cultured in 1640 medium + 10% FBS, and the specific culture method can be according to the conventional method. The test compound BI8622 was formulated with dimethyl sulfoxide (DMSO) as a storage solution with a concentration of 10 mM, and was diluted to a working concentration of 10 uM with 1640 complete medium before treating the cells. The control group was treated with 0.1% DMSO, and the experimental group BI8622 and the control group The treatment time of both groups was 3 hours, and then the subsequent stimulation and detection experiments of i...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The present invention provides a new application of an HUWE1 inhibitor BI8622 to inhibition of inflammasome activation. Researches discover that the HUWE1 inhibitor BI8622 can remarkably reduce activation of cysteine protease-1 (Caspase-1) and expression of interleukin 1 beta (IL-1 beta) in bone marrow derived macrophages (BMDM) of a mouse, and cell death is reduced; and meanwhile, it is proved that the BI8622 can remarkably reduce activation of the Caspase-1 and expression of the IL-1 beta in a human mononuclear macrophage line THP1 and human primary peripheral blood mononuclear cells (PBMC),and cell death is also remarkably reduced, so that the BI8622 can remarkably inhibit inflammasome activation.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to a new application of HUWE1 inhibitor BI8622. Background technique [0002] Inflammasome activation plays an important role in host inflammation, resistance to pathogen invasion, and autoimmune diseases. The classic inflammasomes include NLRP3, AIM2 and NLRC4 inflammasomes, whose activation recognizes different stimuli, and eventually leads to the activation of cellular cysteine ​​protease-1 (Caspase-1), thereby inducing cells to produce mature Interleukin 1β (IL-1β), interleukin 18 (IL-18), and activated caspase-1 can cleave gastrointestinal dermatin D (GSDMD), leading to the occurrence of cell pyroptosis (Inflammasomes: mechanism of action, role in disease, and therapeutics Haitao Guo, Justin B Callaway & Jenny P-Y Ting; Nature Medicine volume 21, pages 677–687 (2015).). Abnormal inflammasome activation is associated with the occurrence of various diseases, and more and more ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): A61K31/506A61P19/06A61P3/10A61P17/00A61P29/00
CPCA61K31/506A61P3/10A61P17/00A61P19/06A61P29/00Y02A50/30
Inventor 齐晓朋徐涛李艺辉郭晓敏
Owner KUNMING INST OF ZOOLOGY CHINESE ACAD OF SCI
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap